This invention relates to novel ribofuranosyl derivatives and methods for preparing same.
Because of the interest in naturally occurring nucleosides, considerable effort has been directed towards synthesizing D-ribofuranosyl derivatives of purines, pyrimidines and other nitrogenous bases. Pentofuranosyl halides are valuable synthetic intermediates for the preparation of nucleosides, nucleoside analogs, and glycosides. Crystalline halides are preferred for this purpose because they can be purified and stored. At present, the most widely used D-ribofuranosyl halides are 2,3,5-tri-O-benzoyl-D-ribofuranosyl chloride and 2,3,5-tri-O-benzoyl-D-ribofuranosyl bromide, both of which are syrups obtained from crystalline precursors, such as 1-O-acetyl-2,3,5-tri-O-benzoyl-.beta.-D-ribofuranose. These syrups are relatively unstable and, consequently cannot be stored, requiring them to be used immediately after preparation. Also, these syrups are difficult to purify. Furthermore, the processes employed to prepare these syrup halides requires several steps. Generally, attempts to prepare crystalline halides have either resulted in the production of syrupy products or require processes which are lengthy and involve several steps.
A principal object of the invention is to provide stable crystalline ribofuranosyl halides suitable for use in the preparation of nucleosides and related compounds and methods for preparing same.
Another object of the invention is to provide a stable crystalline ribofuranosyl precursor to these halides which may be used as intermediates in the preparation of these halides.
A further object of the invention is to provide a simplified method for preparing a stable crystalline ribofuranosyl bromide at relatively high yields.
A still further object of the invention is to provide crystalline derivatives of these halides which can be used as intermediates in the preparation of synthetic nucleosides and glycosides and methods for preparing same.
Other objects, aspects and advantages of the invention will become apparent upon reviewing the following detailed description and the appended claims.
According to the invention, a ribofuranosyl derivative capable of yielding a halide derivative thereof is first formed from methyl-D-ribofuranosyl and this derivative is blocked with a functional group which produces a crystalline derivative. More specifically, methyl-D-ribofuranoside is reacted with a p-nitrobenzoyl halide to effect the p-nitroenzoylation of the three free hydroxyl groups and yield a crystalline methyl-2,3,5-tri-O-(p-nitrobenzoyl)-.beta.-D-ribofuranoside which can be halogenated to yield a crystalline 2,3,5-tri-O-(p-nitrobenzoyl)-.beta.-D-ribofuranosyl halide.
The crystalline halide can be used in the synthesis of nucleosides and glycosides. Further, by cyanating under anhydrous conditions it can yield 2,5-anhydro-3,4,5-tri-O-(p-nitrobenzoyl)-D-allononitrile. Hydrolyzing this allononitrile yields 2,5-anhydro-D-allonic acid and this acid can be reacted with 4,5,6-triamino pyrimidine to yield 8-.beta.-D-ribofuranosyl adenine.
This crystalline halide also can be used to prepare an alpha-halide precursor by first hydrolyzing it to yield the crystalline 2,3,5-tri-O-(p-nitrobenzoyl)-D-ribofuranose and p-nitrobenzoylating this ribofuranose to yield crystalline 1,2,3,5-tetra-O-(p-nitrobenzoyl)-.beta.-D-ribofuranose which can be treated with an equimolar amount of a halide, such as hydrogen bromide in solution to yield an alpha-halide, such as 2,3,5-tri-O-(p-nitrobenzoyl)-.beta.-D-ribofuranosyl bromide. Thus, the novel halides of the invention are the beta or alpha halide precursors for nucleosides.